An estimated 22 million women in the United States have undergone hysterectomy;in 2004, 617,000 of these procedures were performed. Accidental laceration of the bladder during surgery is the most common (incidence of up to 8.3%) complication of hysterectomy. Most of these bladder injuries are repaired by suturing during the surgery, and the bladder is drained with a catheter postoperatively. However, these bladder injuries can result in scar tissue formation. The use of sutures and the formation of scar tissue are especially undesirable because either can compromise the proper distension of the bladder to store urine. In addition, the use of catheters and collecting bags during recovery can severely diminish patients'quality of life. To address these serious health issues, the proposed work will engineer a tissue adhesive that will eliminate the need for suture and will minimize scar formation. The main goal of the proposed research is to design a clinically applicable tissue adhesive that is easy to use (rapid curing, two-component solutions with long shelf life), conforms with stretching of the bladder wall (highly compliant), and degrades with controlled release of bioactive molecules that inhibit scar formation. The investigators will combine their expertise in polymer synthesis, controlled drug/gene delivery, and biomechanics to develop and assess a biodegradable tissue adhesive for repair of bladder tissue injuries using a high-strength, compliant hydrogel system currently in development. Specific aims of the proposed research are 1) To optimize mechanical properties of the bladder tissue adhesives ex vivo, 2) to optimize the scar-inhibiting function of the tissue adhesive ex vivo, and 3) to evaluate the efficacy of the selected scar-inhibiting tissue adhesive in vivo. Tasks involved in achieving these specific aims include, a) tuning the hydrogel tensile properties, cure time, and tissue adhesiveness by adjusting the chemical composition, concentration, molecular weights, and reaction conditions, b) evaluating degradation rate, release kinetics, and efficacy of nucleic acid therapeutics for antagonizing the expression of genes pertinent to scar formation in cultured cells, and c) evaluating the safety and efficacy of the newly designed hydrogel system by evaluating the host response in a rat bladder injury model. These initial in vivo data will be used for further modification of the design and will be the basis for advancing this research to a functional bladder injury model in larger animals. PUBLIC HEALTH RELEVANCE: In the United States, 1/3 of women can expect to have hysterectomy by age 60 and the most common (incidence of up to 8.3%) complication associated with this procedure is accidental nicking of the bladder during surgery. The main goal of the proposed research is to engineer a novel, biodegradable tissue glue for on-the-spot treatment of surgical bladder injuries. The new glue will not only eliminate the need for stitches, catheters, and collecting bags during recovery, but also release therapeutics to block unwanted scar tissues on the bladder during healing, and thus, will help increase the quality of life of many women.